Desethylamiodarone (2-butyl-3-benzofuranyl)[4-[2-(ethylamino)ethoxy]-3,5-diiodophenyl]-methanone, DEA), the major metabolite of the widely used antiarrhythmic drug amiodarone (AM), also has antiarrhythmic activity, significantly increasing the action potential duration (class III antiarrhythmic effect) and decreasing the maximum rate of depolarization (class I antiarrhythmic effect) at clinically relevant concentrations. (1, 2) Amiodarone is widely used in the treatment of a variety of cardiac diseases. (3, 4, 5) Amiodarone and its main metabolite DEA are both strongly bound to plasma proteins. (6) DEA rapidly accumulates in extra cardiac tissues (especially in the lungs) after amiodarone treatment, sometimes in higher concentrations than amiodarone itself. (7, 8, 9, 10) Tissue concentrations of AM and of DEA are 100 to above 1000 times higher than the corresponding plasma concentrations. (11) Organs that store these drugs are adipose tissue, liver and lung, but also skin, pancreas, myocardium and thyroid gland. Except in the adipose tissue, the tissue concentrations of the metabolite are higher than that of the parent drug following chronic administration of AM. (12) Repetitive exposures of cell cultures to AM and DEA respectively resulted in a cumulative and partially saturable drug uptake. Under all conditions tested DEA accumulation was always higher than that of AM. (13) The mean elimination half-life of DEA is 40 days and varies considerably between individuals. (14) Direct and indirect evidence for intralysosomal localization have been presented for AM and DEA in vivo and in vitro. (15) The therapeutic range of amiodarone has been recommended to be <5.7 μM (16). Indeed, it has been reported that the concentrations of amiodarone and DEA in patient plasma are 1.6-5.3 μM and 1.7-4.5 μM, respectively. (17) Amiodarone was found to activate mainly necrotic cell death pathways, whereas DEA also activated apoptotic pathways. (18) DEA may act synergistically with amiodarone. (19) DEA has greater cytotoxic potency in vitro compared to AM (20), however this toxic effect is further enhanced in the presence of amiodarone. To avoid this enhanced toxic effect, as well as to decrease the likeliness of the side effects we will perform our experiments exclusively with DEA. After administration of amiodarone in therapeutic doses, plasma concentration of DEA is in a range of 1.7-4.5 μM (17), however in the lungs DEA can reach mM concentrations due to its significant accumulation in that organ. (21)
Modern surgical techniques and new chemotherapeutic approaches have significantly improved the effectiveness of treatment in primary tumors, but metastasis remains the leading cause of death in patients with cancer. (22) In determining the stage, relevant treatment, and prognosis of most solid cancers metastasis is the key factor. Tumor metastasis is a complex process that involves local invasion, intravasation, and survival in the circulation, extravasation, and colonization. The tumor cells must overcome numerous hurdles to successfully colonize in the target organ (23, 24) Lung metastases are identified in 30-55% of all cancer patients, though prevalence varies based on the type of primary cancer. Almost any cancer has the ability to spread to the lungs, but the tumors that most commonly do so include bladder cancer, colon cancer, breast cancer, prostate cancer, sarcoma, Wilms tumor, and neuroblastoma. (23, 24) The lungs are the most common site of metastasis in melanoma (22). Although metastasis only occurs in approximately 10% of melanoma patients, it remains the major cause of death (25).
The present inventors surprisingly found that DEA has significant anti-tumor effect. Although DEA is a well-known metabolite, which accumulates in lungs, and is capable of inducing apoptotic cell death, no such anti-tumor effect has been suggested.